Styrene-maleic anhydride copolymers (SMA copolymers) are used in numerous applications but their use in bio-applications is hindered by their lack of purity and residual hazardous contaminates.
The FDA approved SMA copolymers as indirect food additives for use as articles or components of articles that contact food items (Code of Federal Regulations, Sec. 177.1820 “Styrene-maleic anhydride copolymers”, Title 21, Volume 3 p 304-305, revised as of Apr. 1, 2000). The FDA specified that SMA copolymers have a minimum average molecular mass of 70,000 and contain not more that 15 weight percent maleic anhydride, 0.3 weight percent residual styrene monomer, 0.1 weight percent residual maleic anhydride monomer, 0.006 weight percent maximum extractible fractions in distillated water at reflux temperature for 1 hr, and 0.02 weight percent maximum extractible fractions in n-heptane at 73° F. for 2 hr.
Sethi, N. et al. demonstrated the biocompatibility of SMA commercial products, but a multistep, complex purification procedure was required before utilization. Sethi, N. et al. Contraception 1989, 39, 217-226. The same conclusion was reported by Lohiya, N. K et al. Lohiya, N. K. et al. Int. J. Androl. 2000, 23, 36-42.
Wagner J. G. et al in U.S. Pat. No. 2,897,121 and Chen, Y. R. et al in Colloids and Surfaces A: Physicochem. Eng. Aspects, 2004, 242, 17-20 present the utilization of SMA copolymers as additives for a pharmaceutical carrier for oral administration. Although the authors assert that the polymers can be used for bio-applications, supporting data, such as purity, is not presented.
Patel, H. A. et al. disclose the synthesis, release study, and antimicrobial properties of acriflavine bound to SMA. Patel, H. A. et al. Die Angewandte Makromolekulare Chemie 1998, 263, 25-30. Patel, H. A. et al. report similar findings for SMA bound ampicillin. Patel, H. A. et al. Die Angewandte Makromolekulare Chemie 1999, 271, 24-27. In both cases, advanced purification of the SMA copolymer was necessary to make the composition suitable for bio-application.
Ottenbrite, R. M. and Spiridon, D. disclose the use of SMA copolymers as antitumor effectors. Ottenbrite, R. M. and Spiridon, D demonstrate the biocompatibility of the SMA copolymers but only after rigorous purification steps. Ottenbrite, R. M. J. Macromol. Sci.-Chem. 1985, A22 (5-7), 819-832; Spiridon D. Polymer International, 1997, 43, 175-181.
U.S. Pat. No. 3,980,663 and U.S. Pat. No. 4,381,784 disclose using SMA copolymers as water absorbing materials for hygienic care. U.S. Pat. No. 3,939,108 and U.S. Pat. No. 6,590,019 disclose SMA copolymers as an adhesive useful for bottle labeling. U.S. Pat. No. 5,080,888 discloses SMA copolymers in cosmetics. U.S. Pat. No. 4,980,403; U.S. Pat. No. 5,104,957; U.S. Pat. No. 5,480,427; and U.S. Pat. No. 6,127,451 disclose using SMA copolymers as biomaterials. U.S. Pat. No. 4,153,682; U.S. Pat. No. 6,500,447; and U.S. Pat. No. 6,531,160 disclose using SMA copolymers in pharmaceutical products as drug delivery systems.
A condition for using SMA copolymers in a bio-application is that its chemical purity be as high as possible, while its hazardous contaminant content be as low as possible. Contamination of SMA copolymers has two causes derived from the polymerization processes used: 1) non-reacted monomers, and 2) auxiliaries of polymerization such as: organic solvents, initiators . . . etc.
For example, SMA copolymers are prepared mainly by solvent based methods, but these methods are also the most contaminating because, besides unreacted monomers and initiators, there is residual solvent to remove. See U.S. Pat. No. 2,286,062; U.S. Pat. No. 2,378,629; U.S. Pat. No. 2,866,775; U.S. Pat. No. 3,157,595; U.S. Pat. Nos. 3,989,586; 4,105,649; and U.S. Pat. No. 4,126,549. The additional purification steps required represent an important economical restriction to using SMA copolymers in bio-applications compared to other category of polymers.
Bulk polymerization is less contaminating than solution polymerization because there are no organic solvents. See Voss, A. et al. in U.S. Pat. No. 2,047,398; Graves, G. D. in U.S. Pat. No. 2,205,882 and Lee Y. C. et al. in U.S. Pat. No. 4,051,311 disclosing maleic anhydride copolymers of styrene, vinyl acetate, and others by bulk polymerization methods, with and without peroxidic initiators. The content of maleic anhydride monomers is less than 55% by weight in the initial mixture of comonomers. Baer, M. in U.S. Pat. No. 2,971,939 presents the synthesis of styrene maleic anhydride copolymers with a content of maleic anhydride less than 12% by weight using bulk polymerization methods. In these disclosures, a mixture of styrene and peroxidic initiator is allowed to homopolymerize until a 3-5% conversion. At this point, maleic anhydride monomer is added at a constant rate to form a maleic anhydride in styrene solution. The SMA copolymer is then extracted from the reaction mass with benzene and ultimately separated from the solution by precipitation with methanol.
Disadvantages with these bulk polymerization methods include a) incomplete conversion of monomers to copolymer due to increasing impedance of diffusion of the reactants to reaction centers because of increasing reaction mass viscosity; b) purification to remove non-reacted monomer is difficult and realized by dissolution into specific solvents (such as acetone or benzene), followed by precipitation, extraction with alcohols or water, and drying; c) generation of large amounts of reaction heat risking explosion; d) handling of reaction mass is difficult; and e) purification solids after precipitation by extraction is neither cost effective nor ecologically friendly.
Cutter, L. A. in U.S. Pat. No. 4,145,375 presents a process for copolymerizing styrene and maleic anhydride which involves a sequence of operations in which maleic anhydride is first gradually admixed with styrene in a mass stage under polymerizing conditions to rapidly form styrene-maleic anhydride polymer. The styrene-rich mixture is then suspended in water and the styrene polymerization completed as in a conventional mass/suspension polymerization system. The suspension step further modifies the polymer by opening the anhydride group to form free carboxylic acid groups on the polymer chain. Following the heating period, the polymerization mixture is cooled; the polymer beads are separated from the water by a solid-bowl centrifuge, and dried in a rotary air drier. The polymers resulted have Mw=100,000-500,000, and the content of residual styrene is between 0.02 and 0.1% by weight. A disadvantage of this process is that the final product is a blend of polystyrene and SMA copolymer, the polystyrene being a major contaminant, with multiple implications making it unfavorable for bio-applications. Similar problems exist for front polymerization which uses excess of styrene. Szalay, J. et al., Macromol. Rapid Commun. 1999, 20, 315-318.
Methods of copolymerization of maleic anhydride and other monomers in an aqueous medium have been disclosed. See Bomer B. et al. in U.S. Pat. No. 4,737,549; Saraydin D. et al. in J. Appl. Polym. Sci. 2001, 79, 1809-1815; Caycara, T. et al. in J. Polym. Sci. A: Polym. Chem. 2001, 39, 277-283; Akkas, P. et al. in J. Appl. Polym. Sci. 2000, 78, 284-289; Sen, M. et al. in Polymer 1999, 40, 913-917; Sen, M. et al. in Polymer 1998, 39, 1165-1172; Karadag, E. et al. in J. Appl. Polym. Sci. 1997, 66, 733-739; Saraydin, D. et al. in Biomaterials 1994, 15, 917-920; and Karadag, E. et al. in Biomaterials 1996, 17, 6770. However, these methods cannot be used for copolymerizing styrene due to the differences in solubility of the two comonomers. Additionally, the resulting polymer will have few carboxylic groups, limiting the number of potential bio-applications.
Copolymerization yields are highest (approximately 95%) when using equimolecular monomer feeds, and with processes that achieve good mass transfer of reactants (such as those achieved by polymerization in organic solvent media). Processes that don't use equimolecular monomer feeds induce a high value of conversion only for the monomer which is present in the least amount. Klumperman, B. et al. Polymer 1993, 34, 1032-1037; Klumperman, B. Macromolecules, 1994, 27, 6100-6101; Klumperman, B. et al. Eur. Polym. J. 1994, 30, 955-960.
The most difficult aspect of purifying SMA copolymers is removal of unreacted styrene because it is an organic compound liquid, insoluble in water, but soluble in organic solvents with high boiling points that make it difficult to dry, even in high vacuum. Boundy, R. H. “Styrene, its polymers, Copolymers and Derivatives,” Reinhold Publishing Corporation, New York, 1952, pp. 860-865.
Unreacted maleic anhydride can be removed by simple hydrolysis with water to form maleic acid which has a high solubility in water (greater than 4.4×105 ppm(wt) at 25° C.; Yaws C. L. in “Chemical Properties Handbook” McGraw-Hill Companies, Inc. New York, 1999), allowing its efficient and economical elimination from copolymers. In addition, the rate of hydrolysis of free maleic anhydride is much higher than that of polymerized maleic anhydride. Ratzch, M. et al. J. Macromol. Sci-Chem. 1987, A24, 949-965; Wang, M. et al. J. AppL. Polym. Sci. 2000, 75, 267-274.